Processes for the preparation of fluorinated benzoic acids

ABSTRACT

An object of the present invention is to provide a commercially advantageous process for preparing a fluoro benzoic acid. The process according to the present invention comprises either alkylating a fluoro benzoic acid of the formula                    
     wherein R 1  is halogen, or reducing a fluoro benzoic acid of the formula                    
     wherein R 1  is as defined above and R 2  is lower alkyl to thereby produce a fluoro benzoic acid represented by the formula                    
     wherein R 1  and R 2  are as defined above.

TECHNICAL FIELD

The present invention relates to a process for preparing a fluorobenzoic acid.

BACKGROUND ART

Benzo heterocyclic derivatives represented by the formula (1) shownbelow have excellent antibacterial activity and are useful asantibacterial agents (Japanese Examined Patent Publication No.96557/1994).

In the formula, R² is C₁₋₆ alkyl. R³ is a 5- to 9-membered saturated orunsaturated heterocyclic ring residue, the heterocyclic ring residueoptionally having one or more substituents. R⁴ is cyclopropyl which maybe substituted by 1 to 3 substituents selected from the group consistingof C₁₋₆ alkyl and halogen; phenyl which may be substituted by 1 to 3substituents selected from the group consisting of C₁₋₆ alkoxy, halogenand hydroxy on the phenyl ring; C₁₋₆ alkyl which may be substituted byhalogen, C₂₋₆ alkanoyloxy or hydroxy; C₂₋₆ alkenyl or thienyl. R ishydrogen or C₁₋₆ alkyl.

More specifically, the benzo heterocyclic derivatives of the formula (1)and salts thereof have excellent antibacterial activities againstvarious gram-positive bacteria and gram-negative bacteria and are usefulfor the treatment of various infectious diseases induced by variousbacteria in human, other animals and fish and also useful as an externalantimicrobial or disinfectant agent for medical instruments and thelike. The benzo heterocyclic derivatives of the formula (1) and saltsthereof show an excellent antibacterial activity against mycoplasma,Pseudomonas aeruginosa, anaerobic bacteria, resistant cells againstvarious antibacterials, clinically isolated strains, and gram negativeand gram positive bacteria such as Enterococcus faecalis andStaphyloccocus pyognes and hence are useful as an antibacterial agentfor the treatment of diseases induced by these microorganisms. The benzoheterocyclic derivatives of the formula (1) and salts thereof show lowtoxicity and less side effect and have characteristic features such asgood absorbability and sustained activity. Furthermore, the benzoheterocyclic derivatives of the formula (1) and salts thereof are usefulfor the treatment of urinary infectious diseases because they are highlyexcreted via urine, and further because of easy excretion via bile, theyare useful for the treatment of intestinal infectious diseases.

According to Japanese Examined Patent Publication No. 96557/1994, thebenzo heterocyclic derivatives of the formula (1) and salts thereof areprepared by using a fluoro benzoic acid of the formula (2)

wherein R² is as defined above and R¹ is halogen.

According to Japanese Examined Patent Publication No. 96557/1994, asshown below in Reaction Scheme A or B, a fluoro benzoic acid of theformula (2) is prepared by using known starting compounds by amultiple-step process comprising five steps. Thus according to theprocess described in Japanese Examined Patent Publication No.96557/1994, a complicated reaction procedure must be carried out toprepare the fluoro benzoic acid of the formula (2). Furthermore, thedesired fluoro benzoic acid of the formula (2) is obtained only in a lowyield of about 8.3%.

wherein R¹ is as defined above, R^(a) is hydrogen or C₁₋₆ alkyl, R^(b)is C₁₋₆ alkyl, and X¹ is halogen.

wherein R² is as defined above and R^(c) is C₁₋₆ alkyl.

Japanese Unexamined Patent Publications Nos. 243692/1990 and 74167/1992and EP319906 disclose a process for preparing a fluoro benzoic acid ofthe formula (2) by using a compound of the formula (A), as shown in thefollowing Reaction Scheme C:

The process, however, necessitates undertaking three steps to preparethe desired fluoro benzoic acid by using the compound of the formula(A). Furthermore, the desired fluoro benzoic acid is obtained only in alow yield of about 7.5%, based on the compound of the formula (A).

Japanese Unexamined Patent Publications Nos. 502452/1991 and 291959/1998and J. Heterocyclic Chem., 27, p1610 (1990) disclose a process forpreparing a fluoro benzoic acid of the formula (2) by using a compoundof the formula (B), as shown in the following Reaction Scheme D:

wherein R^(d) is alkyl.

The process, however, necessitates undertaking seven steps to preparethe desired fluoro benzoic acid by using the compound of the formula(B). Furthermore, the desired fluoro benzoic acid is obtained only in alow yield of about 45.8%, based on the compound of the formula (B).

J. Heterocyclic Chem., 27, p.1611 (1990) and Journal of MedicinalChemistry, 1991, vol.34, No.3, p.1156 disclose a process for preparing afluoro benzoic acid of the formula (2) by using the compound of theformula (C), as shown in the following Reaction Scheme E:

wherein R^(e) is methyl or ethyl.

The process, however, necessitates undertaking four steps to prepare thedesired fluoro benzoic acid by using the compound of the formula (C).Furthermore, the desired fluoro benzoic acid is obtained only in a lowyield of about 25 to 30%, based on the compound of the formula (C).

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide a single step processfor preparing a fluoro benzoic acid of the formula (2) without thenecessity of undertaking multiple steps, the fluoro benzoic acid beingused as an intermediate for preparing a benzo heterocyclic derivative ofthe formula (1) which is useful as an antibacterial agent.

Another object of the present invention is to provide a process forpreparing the fluoro benzoic acid of the formula (2) by a simple andconvenient procedure at low costs, using an easily available compoundwithout using any special reagents.

A further object of the present invention is to provide a process forpreparing the fluoro benzoic acid of the formula (2) in high purity andhigh yield.

A still further object of the present invention is to provide acommercially advantageous process for preparing the fluoro benzoic acidof the formula (2).

In view of such state, the inventors of the present invention carriedout extensive research to achieve the above objects. During theresearch, the present inventors conceived of using as a startingmaterial a fluoro benzoic acid of the formula (3)

wherein R¹ is as defined above. The fluoro benzoic acid of the formula(3) is a compound which is unsubstituted at the 5-position with respectto the carboxyl group.

Izv. Sib. Otd. Akad. Nauk SSSR, Ser. Khim. Nauk, Vol.5, p100 (1975)discloses a process for preparing a compound of the formula (F)comprising reacting a compound of the formula (D) with a Grignardreagent (E), as shown in the following Reaction Scheme F:

The process produces the compound of the formula (F) in a high yield,but it is presumably owing to the chemical structure of the compound ofthe formula (D) used as a starting material. Stated more specifically,the compound of the formula (D) is a compound wherein all the hydrogenatoms on the benzene ring have been replaced by substituents (fluorineatoms and a carboxyl group). Upon substitution reaction with theGrignard reagent (E), a fluorine atom at one of the ortho-positions withrespect to the carboxyl group (i.e., at 2- or 6-position) is substitutedby R^(f). Whether R^(f) replaces either one of the fluorine atoms at the2- and 6-positions with respect to the carboxyl group, the resultingcompound will be a compound represented by the formula (F).

Japanese Examined Patent Publications Nos. 502452/1991 and 291959/1998disclose a process for preparing a compound of the formula (H), whichcomprises reacting a compound of the formula (G) with alkyllithium, asshown in the following Reaction Scheme G:

The process produces the compound of the formula (H) in a high yield,but it is presumably owing to the chemical structure of the compound ofthe formula (G) used as a starting material. Stated more specifically,the compound of the formula (G) is a compound wherein all the hydrogenatoms on the benzene ring have been replaced by substituents (fluorineatoms and a 2-oxazolyl group). Upon substitution reaction withalkyllithium, a fluorine atom at one of the ortho-positions with respectto the 2-oxazolyl group (i.e., 2- or 6-position) is substituted byR^(g). Whether R^(g) replaces either one of the fluorine atoms at the 2-and 6-positions with respect to the 2-oxazolyl group, the resultingcompound will be a compound represented by the formula (H).

From the conventional reactions as described above, it could easily beassumed that when a fluoro benzoic acid of the formula (3), which isunsubstituted at the 5-position with respect to the carboxyl group, isalkylated with a Grignard reagent (E) or alkyllithium, the resultingcompound would have an alkyl group either at the 2-position or at the6-position with respect to the carboxyl group. Stated more specifically,it had been considered that the reaction would produce two kinds ofcompounds, i.e., a compound having an alkyl group at the 2-position, anda compound having an alkyl group at the 6-position, the 2- and6-positions being ortho positions with respect to the carboxyl group ofthe fluoro benzoic acid of the formula (3). Surprisingly, however, thereaction produces only a trace or no amount of the compound having analkyl group at the 6-position, which is one of the ortho positions withrespect to the carboxyl group of the fluoro benzoic acid of the formula(3), and selectively produces only the compound having an alkyl group atthe 2-position, which is the other ortho position with respect to thecarboxyl group of the fluoro benzoic acid of the formula (3). Suchfinding was surprising and unpredictable even to those skilled in theart having chemical knowledge in the field.

The present inventors further found that the object of the invention canalso be achieved by reducing a fluoro benzoic acid of the formula (4)

wherein R¹ and R² are as defined above. The present invention has beenaccomplished based on the above findings.

The present invention provides a process (hereinafter referred to as“process A”) for preparing a fluoro benzoic acid of the formula (2)

wherein R¹ and R² are as defined above,

which comprises alkylating a fluoro benzoic acid of the formula (3)

wherein R¹ is as defined above.

The present invention further provides a process (hereinafter referredto as “process B”) for preparing the fluoro benzoic acid of the formula(2)

wherein R¹ and R² are as defined above,

which comprises reducing a fluoro benzoic acid of the formula (4)

wherein R¹ and R² are as defined above.

In the specification, C₁₋₆ alkyl represented by R² includes C₁₋₆straight chain or branched chain alkyl, such as methyl, ethyl, n-propyl,isopropyl, n-butyl, tert-butyl, n-pentyl, n-hexyl and the like.Particularly preferred C₁₋₆ alkyl represented by R² is methyl.

The halogen represented by R¹ includes fluorine, chlorine, bromine andiodine. Particularly preferred halogen is fluorine or bromine.

First, process A is described.

wherein R¹ and R² are as defined above and M is a group of the formula:—MgX (wherein X is halogen), lithium metal or a group of the formula:ZnX (wherein X is as defined above).

In Reaction Scheme-1, the starting compound of the formula (3) and thealkylating agent of the formula (5) are both known compounds that areeasily available.

The compound of the formula (3) includes 2,3,4,6-tetrafluorobenzoicacid, 2,3,4-trifluoro-6-chlorobenzoic acid,2,3,4-trifluoro-6-bromobenzoic acid and the like. Preferred compounds ofthe formula (3) are 2,3,4,6-tetrafluorobenzoic acid,2,3,4-trifluoro-6-bromobenzoic acid and the like.

The alkylating agent of the formula (5) includes Grignard reagents suchas methyl magnesium bromide, methyl magnesium chloride, methyl magnesiumiodide, ethyl magnesium bromide, ethyl magnesium chloride, ethylmagnesium iodide, n-propyl magnesium bromide, n-propyl magnesiumchloride, n-propyl magnesium iodide, isopropyl magnesium bromide,isopropyl magnesium chloride, isopropyl magnesium iodide, n-butylmagnesium bromide, n-butyl magnesium chloride, n-butyl magnesium iodide,tert-butyl magnesium bromide, tert-butyl magnesium chloride, tert-butylmagnesium iodide, n-pentyl magnesium bromide, n-pentyl magnesiumchloride, n-pentyl magnesium iodide, n-hexyl magnesium bromide, n-hexylmagnesium chloride and n-hexyl magnesium iodide, and the like;alkyllithiums such as methyllithium, ethyllithium, n-propyllithium,isopropyllithium, n-butyllithium, tert-butyllithium, n-pentyllithium,n-hexyllithium and the like; zinc compounds such as methylzinc iodide,ethylzinc iodide, and the like.

Preferred compounds for use as alkylating agent of the formula (5) arethose wherein M is a group of the formula: MgX (Grignard reagents).Especially preferred alkylating agents of the formula (5) are methylmagnesium bromide, methyl magnesium chloride and methyl magnesiumiodide. The alkylating agents may be used singly or in combination oftwo or more.

The reaction between the compound of the formula (3) and the alkylatingagent of the formula (5) is usually carried out in a suitable solvent.The solvent may be any conventional solvents unless they give anyundesirable effect on the reaction. Such solvent includes, for example,aromatic hydrocarbons such as benzene, toluene and xylene; ethers suchas diethyl ether, tetrahydrofuran, dioxane, diethylene glycol dimethylether and t-butyl methyl ether; aliphatic or alicyclic hydrocarbons suchas n-hexane, n-pentane and cyclohexane; and the like; or a mixturethereof.

The proportions of the compound of the formula (3) and the alkylatingagent of the formula (5) are not particularly limited. However, thelatter is usually used in an amount of at least 1 mole, preferably from1 to 5 moles, per mole of the former.

The reaction between the compound of the formula (3) and the alkylatingagent of the formula (5) may be carried out with cooling or at roomtemperature or with heating. The reaction is usually carried out at atemperature of from around −30° C. to around 150° C., preferably fromaround −10° C. to around 70° C., and usually completes in about 1 toabout 20 hours.

The fluoro benzoic acid of the formula (2) obtained by the abovereaction can easily be isolated by conventional separation methods. Suchmethod includes, for example, extraction with solvents, dilution method,recrystallization, column chromatography and preparative thin-layerchromatography.

According to process A, the alkylating agent of the formula (5)selectively reacts with fluorine at the 2-position of the benzene ringof the compound of the formula (3), thus providing the desired fluorobenzoic acid of the formula (2) in a high yield and high purity.

Secondly, process B is described.

wherein R¹ and R² are as defined above.

In Reaction Scheme-2, the starting compound represented by the formula(4) is a known compound that is easily available.

The compound of the formula (4) includes, for example,2,3,4,5-tetrafluoro-6-methylbenzoic acid,2,3,4,5-tetrafluoro-6-ethylbenzoic acid,2,3,4,5-tetrafluoro-6-n-propylbenzoic acid,2,3,4,5-tetrafluoro-6-isopropylbenzoic acid,2,3,4,5-tetrafluoro-6-n-butylbenzoic acid,2,3,4,5-tetrafluoro-6-tert-butylbenzoic acid,2,3,4,5-tetrafluoro-6-n-pentylbenzoic acid,2,3,4,5-tetrafluoro-6-n-hexylbenzoic acid, and the like. Especiallypreferred is 2,3,4,5-tetrafluoro-6-methylbenzoic acid.

The reaction of converting the compound of the formula (4) into thecompound of the formula (2) is carried out by catalytic reduction of thecompound of the formula (4) in the presence of a basic compound in asuitable solvent. The solvent may be any conventional solvents unlessthey give any undesirable effect on the reaction. Such solvent includes,for example, water, acetic acid, alcohols such as methanol, ethanol,isopropanol and polyethylene glycol (PEG); aliphatic or alicyclichydrocarbons such as n-hexane and cyclohexane; ethers such as dioxane,tetrahydrofuran, diethyl ether and diethylene glycol dimethyl ether;esters such as ethyl acetate and methyl acetate; aprotic polar solventssuch as N,N-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP),dimethylacetamide (DMA) and hexamethylphosphoric triamide (HMPA); andthe like; or a mixture of thereof.

The catalyst for catalytic reduction may be selected from a wide rangeof known catalysts, such as palladium, palladium-black,palladium-carbon, palladium hydroxide, palladium hydroxide-carbon,rhodium-carbon, platinum, platinum oxide, copper chromite, Raney nickeland the like. The catalytic reduction catalysts may be used singly or incombination of two or more. Of the catalytic reduction catalysts,especially preferred is palladium hydroxide. The amount of the catalystis not particularly limited but the catalyst is usually used in anamount of from about 0.02 to about 1 times the weight of the compound ofthe formula (4).

The basic compound may be selected from a wide range of known compounds,for example, inorganic bases such as sodium hydroxide, potassiumhydroxide, sodium carbonate, potassium carbonate, sodiumhydrogencarbonate, potassium hydrogencarbonate, cesium hydroxide, cesiumcarbonate, metallic sodium, metallic potassium, metallic magnesium,sodium hydride and sodium amide; metal alcoholates such as sodiummethylate, sodium ethylate, potassium t-butoxide, and organic bases suchas potassium hexamethyldisilazide. The basic compounds may be usedsingly or in combination of two or more. The amount of the basiccompound is not particularly limited. The basic compound is usually usedin an amount of from 1 to 10 moles, preferably from 1 to 5 moles, permole of the compound of the formula (4).

The catalytic reduction reaction may be carried out with cooling or atroom temperature or with heating. The reaction is usually carried out ata temperature of from around −20° C. to around 100° C., preferably fromaround 0° C. to room temperature at a hydrogen pressure of from 1 to 10atm. The reaction is usually completed in about 0.5 to about 10 hours.

A reaction accelerator may be added to the catalytic reduction reactionsystem. Such reaction accelerator includes, for example, crown etherssuch as 12-crown-4, 15-crown-5, 18-crown-6 and dibenzo-18-crown-6;polyoxyamines such as tris [2-(2-methoxyethoxy)ethyl]amine; polyaminessuch as pentaethylenetetramine and pentaethylenehexamine; and the like.The reaction accelerators may be used singly or in combination of two ormore.

The fluoro benzoic acid of the formula (2) obtained by the abovereduction reaction can easily be isolated by conventional separationmethods. Such method includes, for example, extraction with solvents,dilution method, recrystallization, column chromatography andpreparative thin-layer chromatography.

The fluoro benzoic acid of the formula (2) prepared according to theprocess of the present invention can be converted into a benzoheterocyclylic derivative (1) useful as an antibacterial agent,according to the process shown below in Reaction Scheme-3 and inReaction Scheme-4.

wherein R¹, R² and R⁴ are as defined above, R⁵ is a group of theformula: —COR¹⁰ (wherein R¹⁰ is C₁₋₆ alkyl) or —COOR¹¹ (wherein R¹¹ ishydrogen, C₁₋₆ alkyl or a metal such as sodium, potassium, lithium, 1/2magnesium or 1/2 zinc), R⁶ is C₁₋₆ alkyl, R⁷ is a group of the formula:—NR¹²R¹³ (wherein R¹² and R¹³ are each C₁₋₆ alkyl) or C₁₋₆ alkoxy, X² ishalogen, and R⁸ and R⁹ are each C₁₋₆ alkyl.

The halogenation of the compound of the formula (2) is carried out byreacting the compound of the formula (2) with a halogenating agent inthe presence or absence of a solvent. The solvent includes esters suchas ethyl acetate and methyl acetate; aromatic hydrocarbons such asbenzene, toluene and xylene; halogenated hydrocarbons such asdichloromethane, chloroform and carbon tetrachloride; ethers such asdioxane, tetrahydrofuran and diethyl ether; DMF, dimethylsulfoxide(DMSO); and the like. The halogenating agent may be any conventionalhalogenating agents which can convert hydroxy in a carboxyl group into ahalogen atom. The halogenating agent includes, for example, thionylchloride, phosphorus oxychloride, phosphorus oxybromide, phosphoruspentachloride, phosphorus pentabromide, and the like. The proportions ofthe compound (2) and the halogenating agent are not particularly limitedand may be suitably selected from a wide range, but, in case of using nosolvents, the halogenating agent is usually used in a large excessamount, and in case of using a solvent, the halogenating agent isusually used in an amount of at least 1 mole, preferably 2 to 4 molesper mole of the compound (2). The reaction temperature and reactionperiod of time are not particularly limited, either, but the reaction isusually carried out at a temperature of from room temperature to around100° C. for about 30 minutes to about 6 hours.

The reaction between the compound of the formula (6) and the compound ofthe formula (7) is carried out in the presence of a basic compound in asuitable solvent. The solvent used in the reaction may be anyconventional solvents unless they give any undesirable effect on thereaction. The solvent includes, for example, ethers such as diethylether, dioxane, tetrahydrofuran, monoglyme and diglyme; alcohols such asmethanol, ethanol and isopropanol; aromatic hydrocarbons such asbenzene, toluene and xylene; aliphatic or alicyclic hydrocarbons such asn-hexane, n-heptane, cyclohexane and ligroin; amines such as pyridineand N,N-dimethylaniline; halogenated hydrocarbons such as chloroform,dichloromethane and carbon tetrachloride; esters such as ethyl acetateand methyl acetate; aprotic polar solvents such as DMF, DMSO and HMPA;or a mixture of thereof. The basic compounds employed in the reactionincludes inorganic bases such as metallic sodium, metallic potassium,metallic magnesium, sodium hydride, sodium amide, sodium hydroxide,potassium hydroxide, sodium carbonate, potassium carbonate, sodiumhydrogencarbonate and magnesium chloride; metal alcoholates such assodium methylate and sodium ethylate, and organic bases such aspyridine, piperidine, quinoline, triethylamine and N,N-dimethylaniline.The basic compounds may be used singly or in combination of two or more.The reaction is usually carried out at a temperature of from around 0°C. to around 150° C., preferably from around 0° C. to around 120° C. Thereaction is usually completed in about 0.5 to about 20 hours. Theproportions of the compound of the formula (6) and the compound of theformula (7) are such that the latter is usually used in an amount of atleast 1 mole, preferably 1 to 2 moles, per mole of the former. The basiccompound is usually used in an amount of at least 1 mole, preferably 1to 2 moles, per mole of the compound of the formula (6).

When the compound of the formula (8) is a compound wherein R⁵ is thegroup of the formula: —COR¹⁰, the reaction for removal of the group:—COR¹⁰ from the compound is carried out in a suitable solvent in thepresence of a basic compound. The solvent used in the reaction includes,for example, ethers such as diethyl ether, dioxane, tetrahydrofuran,monoglyme and diglyme; aromatic hydrocarbons such as benzene, tolueneand xylene; aliphatic or alicyclic hydrocarbons such as n-hexane,n-heptane and cyclohexane; aprotic polar solvents such as DMF, DMSO,HMPA, and the like. The basic compound includes ammonia gas, aqueousammonia, ammonium salts such as ammonium chloride, primary or secondaryamines such as ethylamine, diethylamine and piperidine, and the like.The reaction is usually carried out at a temperature of from around 0°C. to around 150° C., preferably from room temperature to around 100° C.The reaction is usually completed in about 1 to about 20 hours.

When the compound of the formula (8) is a compound wherein R⁵ is a groupof the formula: —COOR¹¹, the reaction for removal of the group —COOR¹¹from the compound is carried out in an aqueous solution in the presenceof an acid catalyst. The acid catalyst used in the reaction includesmineral acids such as hydrochloric acid and sulfuric acid and organicacids such as p-toluene sulfonic acid. The reaction is usually carriedout at a temperature of from around 0° C. to around 150° C., preferablyfrom room temperature to around 100° C. The reaction is usuallycompleted in about 1 to about 20 hours.

The reaction between the obtained R⁵ group-removed compound and thecompound of the formula (9) is carried out in a suitable solvent. Thesolvent employed in the reaction may be any solvents which are used inthe above reaction for the removal of the R⁵ group (COR¹⁰ group) inaddition to anhydrous alkanoic acids such as acetic anhydride, esterssuch as ethyl acetate and methyl acetate, and the like. The reaction isusually carried out at a temperature of from around 0° C. to around 200°C., preferably from around 0° C. to around 150° C. The reaction isusually completed in about 0.5 to about 10 hours. The compound of theformula (9) is used in an equimolar to large excess amount, preferablyin an equimolar to 2-fold molar amount, based on the compound of theformula (8). In case of using a compound of the formula (9) wherein R⁷is C₁₋₆ alkoxy, the reaction may also be carried out by using acidanhydrides such as acetic anhydride as solvents as well as theabove-mentioned solvents. The reaction is usually carried out at atemperature of from around 0° C. to around 200° C., preferably at fromaround 0° C. to around 170° C.

The reaction between the compound of the formula (10) and the compoundof the formula (11) is carried out in a suitable solvent. The solventemployed in the reaction may be any conventional solvents unless theygive any undesirable effect on the reaction. The solvent used in thereaction includes, for example, alcohols such as methanol, ethanol andpropanol; ethers such as diethyl ether, dioxane, tetrahydrofuran,monoglyme and diglyme; aromatic hydrocarbons such as benzene, tolueneand xylene; aliphatic or alicyclic hydrocarbons such as n-hexane,n-heptane, cyclohexane and ligroin; halogenated hydrocarbons such aschloroform, methylene chloride and carbon tetrachloride; and aproticpolar solvents such as acetonitrile, DMF, DMSO, HMPA, NMP and1,3-dimethyl-2-imidazolidinone (DMI), and the like. The compound of theformula (11) is usually used in an amount of at least 1 mole, preferably1 to 2 moles, per mole of the compound of the formula (10). The reactionis usually carried out at a temperature of from around −20° C. to around150° C., preferably from around 0° C. to around 100° C., and usuallycompleted in about 0.1 to about 15 hours. In the reaction, a basiccompound may optionally be added to the reaction system. Such basiccompound may be any basic compounds which are used for the reaction ofconverting the compound of the formula (6) to the compound of theformula (7) as shown in Reaction Scheme-3.

The cyclization reaction of the compound of the formula (12) is carriedout in a suitable solvent in the presence of a basic compound. Thesolvent employed in the reaction may be any conventional solvents unlessthey give any undesirable effect on the reaction. The solvent includes,for example, ethers such as diethyl ether, dioxane, tetrahydrofuran,monoglyme and diglyme; aliphatic or alicyclic hydrocarbons such asn-hexane, n-heptane and ligroin; halogenated hydrocarbons such aschloroform, methylene chloride and carbon tetrachloride; aprotic polarsolvents such as acetonitrile, DMF, DMSO, HMPA, NMP and DMI; and thelike. The basic compounds employed in the reaction includes inorganicbases such as metallic sodium, metallic potassium, sodium hydride,sodium amide, sodium hydroxide, potassium hydroxide, sodium carbonateand potassium carbonate; metal alcoholates such as sodium methylate andsodium ethylate, organic bases such as 1,8-diazabicyclo[5,4,0]undecene-7(DBU), N-benzyltrimethylammonium hydroxide and tetrabutylammoniumhydroxide; and the like. The basic compound is usually used in an amountof at least 1 mole, preferably 1 to 2 moles, per mole of the compound ofthe formula (12). The reaction is usually carried out at a temperatureof from around 0° C. to around 200° C., preferably from room temperatureto around 150° C. The reaction is usually completed in about 0.5 toabout 15 hours.

The hydrolysis reaction of the compound of the formula (13) can becarried out under the conditions of conventional hydrolysis, forinstance, in the presence of a basic compound in a solvent. The basiccompound includes, for example, sodium hydroxide, potassium hydroxide,barium hydroxide or potassium carbonate; a mineral acid such as sulfuricacid, hydrochloric acid or nitric acid; or an organic acid such asacetic acid or aromatic sulphonic acids. The solvent includes, forexample, alcohols such as water, methanol, ethanol and isopropanol;ketones such as acetone and methyl ethyl ketone; ethers such as dioxaneand ethylene glycol diethyl ether; acetic acid or a mixture of thereof.The reaction is usually carried out at a temperature of from roomtemperature to around 200° C., preferably from room temperature toaround 150° C. The reaction is usually completed in about 0.1 to about30 hours.

By the reaction, there is produced the compound of the formula (14).

wherein R², R³, R⁴ and R are as defined above.

The compound of the formula (15) includes the compound of the formula(13) and the compound of the formula (14) obtained in Reaction Scheme-3.

In the reaction between the compound of the formula (15) and thecompound of the formula (16), the proportions of the compounds are notparticularly limited and may be selected from a wide range. However, thelatter is usually used in an amount of at least 1 mole, preferably about1 to 5 moles, per mole of the former. The reaction is carried out in aninert solvent. The inert solvent includes, for example, water; alcoholssuch as methanol, ethanol, isopropanol, butanol, amyl alcohol andisoamyl alcohol; aromatic hydrocarbons sush as benzene, toluene andxylene; ethers such as tetrahydrofuran, dioxane and diglyme; dimethylacetamide, acetonitrile, DMF, DMSO, HMPA and NMP; and the like; or amixture thereof. Among these solvents, preferred are acetonitrile, DMF,DMSO, HMPA and NMP. The reaction may also be carried out in the presenceof a deacidification agent. The deacidification agent includes, forexample, inorganic carbonates such as sodium carbonate, potassiumcarbonate, sodium hydrogencarbonate and potassium hydrogencarbonate; andorganic bases such as pyridine, quinoline and triethylamine. Alkaliinemetal halides such as potassium fluoride and lithium chloride andalkaline earth metal halides such as magnesium chloride may also beadded to the reaction system. The reaction is usually carried out undera pressure of from 1 to 20 atom, preferably from 1 to 10 atom, at atemperature of from room temperature to around 250° C., preferably fromroom temperature to around 200° C. The reaction is usually completed inabout 10 minutes to about 30 hours.

When the compound of the formula (1) is a compound wherein R is C₁₋₆alkyl, the compound can be hydrolyzed to the corresponding compound ofthe formula (1) wherein R is hydrogen. The hydrolysis can be carried outunder reaction conditions similar to those used for the hydrolysis ofthe compound (13) shown in Reaction Scheme-3.

The compounds obtained according to the above Reaction Schemes caneasily be isolated by conventional separation methods. Such methodincludes, for example, extraction with solvents, dilution method,recrystallization, column chromatography and preparative thin-layerchromatography.

The single step process according to the present invention produces afluoro benzoic acid of the formula (2) in high purity and high yield atlow costs on a commercial scale by a simple and convenient procedure,without the necessity of undertaking multiple steps, the fluoro benzoicacid being used as an intermediate for preparing a benzo heterocyclicderivative of the formula (1) which is useful as an antibacterial agent.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is described below in more detail with referenceto Examples and Reference Examples.

Example 1

200 mg of 2,3,4,6-tetrafluorobenzoic acid was dissolved in 10 ml ofdiethyl ether and cooled to −10° C. in an argon atmosphere. Then 1.72 mlof a methyl magnesium bromide-diethyl ether solution (3 moles/liter) wasadded dropwise. After completion of dropwise addition, the reactionmixture was heated to room temperature and stirred at room temperaturefor 17 hours. The reaction mixture was added to about 50 ml of coldwater and adjusted to pH 1 with concentrated hydrochloric acid. Thereaction mixture was extracted with ethyl acetate and separated intoliquids. The organic layer was separated, dried over anhydrous sodiumsulfate and concentrated to give 181 mg of3,4,6-trifluoro-2-methylbenzoic acid (yield: 92%).

Purity: 98%, m.p.: 104.0° C.-105.0° C., white granular crystals.

Example 2

To a solution of 1.04 g of 2,3,4,5-tetrafluoro-6-methylbenzoic acid in15 ml of ethanol were added 840 mg of potassium hydroxide, 232 mg ofpentaethylene hexamine and 200 mg of 20% palladium hydroxide. Themixture was stirred in a hydrogen atmosphere at room temperature for 3hours. After addition of water, the reaction mixture was filtratedthrough celite and the filtrate was washed with diethyl ether. Theaqueous layer was adjusted to pH 1 with concentrated hydrochloric acidand extracted with dichloromethane. After evaporating the solvent, theresidue was purified by silica gel column chromatography (eluent; ethylacetate:n-hexane=1:3) to give 761 mg of 3,4,6-trifluoro-2-methylbenzoicacid (yield: 80%).

Purity: 98%, m.p.: 104.0° C.-105.0° C., white granular crystals.

Reference Example 1

7 ml of thionyl chloride was added to 3.2 g of2-methyl-3,4,6-trifluorobenzoic acid, followed by heating and refluxingfor 1 hour. The reaction mixture was concentrated, giving 3.3 g of2-methyl-3,4,6-trifluorobenzoyl chloride. Then 5 ml of toluene was addedto the resulting 2-methyl-3,4,6-trifluorobenzoyl chloride to give atoluene solution.

Separately, 0.9 ml of absolute ethanol and two drops of carbontetrachloride were added to 0.4 g of metallic magnesium. When a reactionbegan, a mixture of 2.6 ml of diethyl malonate, 1.6 ml of absoluteethanol and 6 ml of toluene was added dropwise to the reaction mixtureat a temperature not higher than 60° C., followed by stirring at 60° C.for 1 hour to give ethoxymagnesium ethyl malonate.

To a solution containing ethoxymagnesium ethyl malonate was addeddropwise the toluene solution of 2-methyl-3,4,6-trifluorobenzoylchloride prepared above at a temperature not higher than 0° C. Afterstirring for 30 minutes, a mixture of 0.4 ml of concentrated sulfuricacid and 6 ml of water was added, followed by extraction with diethylether. The extract was dried over magnesium sulfate and concentrated togive 5.2 g of diethyl 2-methyl-3,4,6-trifluorobenzoylmalonate.

Reference Example 2

To 5.1 g of diethyl 2-methyl-3,4,6-trifluorobenzoylmalonate were added20 ml of water and 30 mg of p-toluenesulfonic acid, followed by heatingand refluxing for 2.5 hours. After cooling, the mixture was extractedwith diethyl ether. The extract was dried over magnesium sulfate andconcentrated to give 3.3 g of ethyl2-methyl-3,4,6-trifluorobenzoylacetate.

Reference Example 3

To 3.2 g of ethyl 2-methyl-3,4,6-trifluorobenzoylacetate were added 3.0g of acetic anhydride and 2.7 g of ethyl orthoformate, followed byheating and refluxing for 1 hour. The resulting mixture was concentratedto give 3.5 g of ethyl2-(2-methyl-3,4,6-trifluorobenzoyl)-3-ethoxyacrylate.

Reference Example 4

3.5 g of ethyl 2-(2-methyl-3,4,6-trifluorobenzoyl)-3-ethoxyacrylate wasdissolved in 25 ml of ethanol, and thereto 0.84 ml of cyclopropylaminewas added dropwise under ice-cooling. After stirring at room temperaturefor 30 minutes, the reaction mixture was concentrated. The residue waspurified by silica gel column chromatography (eluent; dichloromethane :n-hexane=1:1) to give 2.7 g of ethyl2-(2-methyl-3,4,6-trifluorobenzoyl)-3-cyclopropylaminoacrylate.

Reference Example 5

2.6 g of ethyl2-(2-methyl-3,4,6-trifluorobenzoyl)-3-cyclopropylaminoacrylate wasdissolved in 26 ml of anhydrous dioxane, and thereto 0.38 g of 60%sodium hydride was added portionwise under ice-cooling. After stirringat room temperature for 30 minutes, the mixture was poured into icewater and extracted with dichloromethane. The extract was dried overmagnesium sulfate and concentrated. Diethyl ether was added to theresidue and the resulting crystals were filtered, followed byrecrystallization from ethanol to give 2.0 g of ethyl1-cyclopropyl-6,7-difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate.

m.p.: 185° C.-187° C.

Reference Example 6

20 ml of 90% acetic acid and 5 ml of concentrated hydrochloric acid wereadded to 1.9 g of ethyl1-cyclopropyl-6,7-difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate,followed by refluxing for 2 hours. After cooling, the crystalsprecipitated were collected by filtration and washed with water,followed by washing with ethanol and then with diethyl ether to give 1.6g of1-cyclopropyl-6,7-difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid.

m.p.: 294° C.-298° C., colorless needles

¹H-NMR (CF₃COOD) δ ppm: 1.43-1.55 (2H, m), 1.65-1.81 (2H, m), 3.06 (3H,d, J=2.8 Hz), 4.08-4.20 (1H, m), 8.40 (1H, dd, J=6.8 Hz, 10.3 Hz), 9.46(1H, s).

Reference Example 7

0.65 g of 2-methylpiperazine was added to a solution of 0.48 g of1-cyclopropyl-6,7-difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid in 5 ml of N-methyl-2-pyrrolidone, followed by heating at 90° C.for 20 minutes. After distilling off the solvent under reduced pressure,the residue was added with ethanol. The resulting crystals were filteredand recrystallized from ethyl acetate-ethanol to give 231 mg of1-cyclopropyl-6-fluoro-7-(3-methyl-1-piperazinyl)-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid.

m.p.: 206° C.-208° C., white powder

Reference Example 8

To a suspension of 1.23 g of ethyl1-cyclopropyl-6,7-difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylateand 254 mg of lithium chloride in acetonitrile was added 1.00 g of2-methylpiperazine, followed by heating and refluxing for 4 hours. Afteradding 24 ml of warm water, the reaction mixture was allowed to cool toprecipitate crystals and the resulting crystals were filtered and washedwith water. The crystals were suspended in 8 ml of isopropyl alcohol and8 ml of 1N-NaOH, followed by stirring at a temperature in the range of50° C. to 60° C. for 1 hour. After evaporating the isopropyl alcohol, tothe residue were added 40 ml of water and 1.24 ml of concentratedhydrochloric acid, followed by washing with dichloromethane. The aqueouslayer was heated at 100° C. for 1 hour to distill off the residualdichloromethane. After the aqueous layer was allowed to cool, 1.04 g ofsodium hydrogencarbonate was added and heated with stirring at 60° C.for 1 hour, thereby neutralizing the aqueous layer. The aqueous layerwas allowed to cool again, followed by stirring at 0° C. for 1 hour. Theresulting crystals were filtered, washed with water and dried at 80° C.for 16 hours to give 1.40 g of1-cyclopropyl-6-fluoro-7-(3-methyl-1-piperazinyl)-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid.

m.p.: 206° C.-208° C., white powder

What is claimed is:
 1. A process for preparing a fluoro benzoic acid ofthe formula (2)

wherein R¹ is halogen and R² is C₁₋₆ alkyl, which comprises alkylating afluoro benzoic acid of the formula (3)

wherein R¹ is as defined above.
 2. The process according to claim 1wherein the alkylating agent used for alkylation is a compoundrepresented by the formula (5) R²M wherein R² is as defined above, and Mis a group of the formula: —MgX (wherein X is halogen), lithium metal ora group of the formula: ZnX (wherein X is as defined above).
 3. Theprocess according to claim 2 wherein the alkylating agent is a compoundrepresented by the formula R²MgX wherein R² and X are as defined above.4. The process according to claim 2 wherein R² in the formula (5) ismethyl.
 5. The process according to claim 2 wherein the alkylating agentis used in an amount of at least 1 mole, per mole of the fluoro benzoicacid of the formula (3).
 6. The process according to claim 2 wherein thealkylating agent is used in an amount of from 1 to 5 moles, per mole ofthe fluoro benzoic acid of the formula (3).
 7. The process according toclaim 1 wherein R¹ in the formula (3) is fluorine, chlorine or bromine.8. The process according to claim 1 wherein R¹ in the formula (3) isfluorine or bromine.
 9. The process according to claim 1 wherein thereaction temperature is in the range of −30° C. to 150° C.
 10. Theprocess according to claim 1 wherein the reaction temperature is in therange of −10° C. to 70° C.
 11. A process for preparing a fluoro benzoicacid of the formula (2)

wherein R¹ is halogen and R² is C₁₋₆ alkyl, which comprises reducing afluoro benzoic acid of the formula (4)

wherein R¹ and R² are as defined above.
 12. The process according toclaim 11 wherein the fluoro benzoic acid of the formula (4) is reducedin the presence of a basic compound, using a catalyst for catalyticreduction.
 13. The process according to claim 12 wherein the catalystfor catalytic reduction is at least one member selected from the groupconsisting of palladium, palladium-black, palladium-carbon, palladiumhydroxide, palladium hydroxide-carbon, rhodium-carbon, platinum,platinum oxide, copper chromite and Raney nickel.
 14. The processaccording to claim 12 wherein the catalyst for catalytic reduction ispalladium hydroxide.
 15. The process according to claim 12 wherein thecatalyst for catalytic reduction is used in an amount of from 0.02 to 1times the weight of the fluoro benzoic acid of the formula (4).
 16. Theprocess according to claim 11 wherein the catalytic reduction is carriedout at a hydrogen pressure of from 1 to 10 atom.
 17. The processaccording to claim 11 wherein the catalytic reduction is carried out ata temperature of from −20° C. to 100° C.
 18. The process according toclaim 11 wherein the catalytic reduction is carried out at a temperatureof from 0° C. to room temperature.